Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner

Oncogene volume 38, pages 5321–5337 (2019)Cite this article

Subjects

A Correction to this article was published on 31 July 2019

Abstract

In IBD patients, integration between a hyper-activated immune system and epithelial cell plasticity underlies colon cancer development. However, molecular regulation of such a circuity remains undefined. Claudin-1 (Cld-1), a tight-junction integral protein deregulation alters colonic epithelial cell (CEC) differentiation, and promotes colitis severity while impairing colitis-associated injury/repair. Tumorigenesis is a product of an unregulated wound-healing process and therefore we postulated that upregulated Cld-1 levels render IBD patients susceptible to the colitis-associated cancer (CAC). Villin Cld-1 mice are used to carryout overexpressed studies in mice. The role of deregulated Cld-1 expression in CAC and the underlying mechanism was determined using a well-constructed study scheme and mouse models of DSS colitis/recovery and CAC. Using an inclusive investigative scheme, we here report that upregulated Cld-1 expression promotes susceptibility to the CAC and its malignancy. Increased mucosal inflammation and defective epithelial homeostasis accompanied the increased CAC in Villin-Cld-1-Tg mice. We further found significantly increased levels of protumorigenic M2 macrophages and β-cateninSer552 (β-CatSer552) expression in the CAC in Cld-1Tg vs. WT mice. Mechanistic studies identified the role of PI3K/Akt signaling in Cld-1-dependent activation of the β-CatSer552, which, in turn, was dependent on proinflammatory signals. Our studies identify a critical role of Cld-1 in promoting susceptibility to CAC. Importantly, these effects of deregulated Cld-1 were not associated with altered tight junction integrity, but on its noncanonical role in regulating Notch/PI3K/Wnt/ β-CatSer552 signaling. Overall, outcome from our current studies identifies Cld-1 as potential prognostic biomarker for IBD severity and CAC, and a novel therapeutic target.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Sengupta N, Yee E, Feuerstein JD. Colorectal cancer screening in inflammatory bowel disease. Dig Dis Sci. 2016;61:980–9.

    Article  Google Scholar 

  2. Landy J, Ronde E, English N, Clark SK, Hart AL, Knight SC. et al. Tight junctions in inflammatory bowel diseases and inflammatory bowel disease associated colorectal cancer. World J Gastroenterol. 2016;22:3117–26.

    Article  CAS  Google Scholar 

  3. Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93:525–69.

    Article  Google Scholar 

  4. Pope JL, Bhat AA, Sharma A, Ahmad R, Krishnan M, Washington MK. et al. Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling. Gut. 2014;63:622–34.

    Article  CAS  Google Scholar 

  5. Dhawan P, Singh AB, Deane NG, No Y, Shiou SR, Schmidt C. et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J Clin Invest. 2005;115:1765–76.

    Article  CAS  Google Scholar 

  6. Pope JL, Ahmad R, Bhat AA, Washington MK, Singh AB, Dhawan P. et al. Claudin-1 overexpression in intestinal epithelial cells enhances susceptibility to adenamatous polyposis coli-mediated colon tumorigenesis. Mol Cancer. 2014;13:167

    Article  Google Scholar 

  7. Ouban A. Claudin-1 role in colon cancer: an update and a review. Histol Histopathol. 2018;33:1013–19.

    PubMed  Google Scholar 

  8. Liu L, Rao JN, Zou T, Xiao L, Smith A, Zhuang R. et al. Activation of Wnt3a signaling stimulates intestinal epithelial repair by promoting c-Myc-regulated gene expression. Am J Physiol Cell Physiol. 2012;302:C277–85.

    Article  CAS  Google Scholar 

  9. Deitrick J, Pruitt WM. Wnt/beta catenin-mediated signaling commonly altered in colorectal cancer. Prog Mol Biol Transl Sci. 2016;144:49–68.

    Article  CAS  Google Scholar 

  10. Sabatino L, Pancione M, Votino C, Colangelo T, Lupo A, Novellino E. et al. Emerging role of the beta-catenin-PPARgamma axis in the pathogenesis of colorectal cancer. World J Gastroenterol. 2014;20:7137–51.

    Article  Google Scholar 

  11. Goretsky T, Bradford EM, Ryu H, Tahir M, Moyer MP, Gao T. et al. A cytosolic multiprotein complex containing p85alpha is required for beta-Catenin activation in colitis and colitis-associated cancer. J Biol Chem. 2016;291:4166–77.

    Article  CAS  Google Scholar 

  12. Miwa N, Furuse M, Tsukita S, Niikawa N, Nakamura Y, Furukawa Y. Involvement of claudin-1 in the beta-catenin/Tcf signaling pathway and its frequent upregulation in human colorectal cancers. Oncol Res. 2001;12:469–76.

    Article  CAS  Google Scholar 

  13. Shiou S-R, Singh AB, Moorthy K, Datta PK, Washington MK, Beauchamp RD. et al. Smad4 regulates Claudin-1 expression in a transforming growth factor-β-independent manner in colon cancer cells. Cancer Res. 2007;67:1571–9.

    Article  CAS  Google Scholar 

  14. Clapper ML, Cooper HS, Chang WC. Dextran sulfate sodium-induced colitis-associated neoplasia: a promising model for the development of chemopreventive interventions. Acta Pharmacol Sin. 2007;28:1450–9.

    Article  CAS  Google Scholar 

  15. Liu Y, Cao X. The origin and function of tumor-associated macrophages. Cell Mol Immunol. 2015;12:1–4.

    Article  Google Scholar 

  16. Waniczek D, Lorenc Z, Snietura M, Wesecki M, Kopec A, Muc-Wierzgon M. Tumor-associated macrophages and regulatory T cells infiltration and the clinical outcome in colorectal cancer. Arch Immunol Ther Exp (Warsz). 2017;65:445–54.

    Article  CAS  Google Scholar 

  17. Hermiston ML, Gordon JI. Inflammatory bowel disease and adenomas in mice expressing a dominant negative N-cadherin. Science. 1995;270:1203–7.

    Article  CAS  Google Scholar 

  18. Sebio A, Kahn M, Lenz HJ. The potential of targeting Wnt/beta-catenin in colon cancer. Expert Opin Ther Targets. 2014;18:611–5.

    Article  CAS  Google Scholar 

  19. Lee G, Goretsky T, Managlia E, Dirisina R, Singh AP, Brown JB. et al. Phosphoinositide 3-kinase signaling mediates beta-catenin activation in intestinal epithelial stem and progenitor cells in colitis. Gastroenterology. 2010;139:869–81.81 e1–9.

    Article  CAS  Google Scholar 

  20. Villegas SN, Gombos R, Garcia-Lopez L, Gutierrez-Perez I, Garcia-Castillo J, Vallejo DM. et al. PI3K/Akt cooperates with oncogenic Notch by inducing nitric oxide-dependent inflammation. Cell Rep. 2018;22:2541–9.

    Article  CAS  Google Scholar 

  21. Breynaert C, Vermeire S, Rutgeerts P, Van Assche G. Dysplasia and colorectal cancer in inflammatory bowel disease: a result of inflammation or an intrinsic risk?. Acta Gastroenterol Belg. 2008;71:367–72.

    CAS  PubMed  Google Scholar 

  22. Low D, Mino-Kenudson M, Mizoguchi E. Recent advancement in understanding colitis-associated tumorigenesis. Inflamm Bowel Dis. 2014;20:2115–23.

    Article  Google Scholar 

  23. Terzic J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010;138:2101–14 e5.

    Article  CAS  Google Scholar 

  24. Dave M, Loftus EV Jr. Mucosal healing in inflammatory bowel disease—a true paradigm of success? Gastroenterol Hepatol (NY). 2012;8:29–38.

    Google Scholar 

  25. Ullman TA, Itzkowitz SH. Intestinal inflammation and cancer. Gastroenterology. 2011;140:1807–16.

    Article  CAS  Google Scholar 

  26. Stidham RW, Higgins PDR. Colorectal cancer in inflammatory bowel disease. Clin Colon Rectal Surg. 2018;31:168–78.

    Article  Google Scholar 

  27. Gonzalez AC, Costa TF, Andrade ZA, Medrado AR. Wound healing—a literature review. Bras Dermatol. 2016;91:614–20.

    Article  Google Scholar 

  28. Neal MD, Richardson WM, Sodhi CP, Russo A, Hackam DJ. Intestinal stem cells and their roles during mucosal injury and repair. J Surg Res. 2011;167:1–8.

    Article  CAS  Google Scholar 

  29. Ormanns S, Neumann J, Horst D, Kirchner T, Jung A. WNT signaling and distant metastasis in colon cancer through transcriptional activity of nuclear beta-Catenin depend on active PI3K signaling. Oncotarget. 2014;5:2999–3011.

    Article  Google Scholar 

  30. Brown JB, Cheresh P, Goretsky T, Managlia E, Grimm GR, Ryu H. et al. Epithelial phosphatidylinositol-3-kinase signaling is required for beta-catenin activation and host defense against Citrobacter rodentium infection. Infect Immun. 2011;79:1863–72.

    Article  CAS  Google Scholar 

  31. Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE. et al. BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis. Gut. 2017;66:852–62.

    Article  CAS  Google Scholar 

  32. Ahmad R, Kumar B, Chen Z, Chen X, Muller D, Lele SM. et al. Loss of claudin-3 expression induces IL6/gp130/Stat3 signaling to promote colon cancer malignancy by hyperactivating Wnt/beta-catenin signaling. Oncogene. 2017;36:6592–604.

    Article  CAS  Google Scholar 

  33. Mendes RD, Canté-Barrett K, Pieters R, Meijerink JPP. The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia. Haematologica. 2016;101:1010–7.

    Article  CAS  Google Scholar 

  34. Wong GW, Knowles GC, Mak TW, Ferrando AA, Zúñiga-Pflücker JC. HES1 opposes a PTEN-dependent check on survival, differentiation, and proliferation of TCRβ-selected mouse thymocytes. Blood. 2012;120:1439–48.

    Article  CAS  Google Scholar 

  35. He XC, Yin T, Grindley JC, Tian Q, Sato T, Tao WA. et al. PTEN-deficient intestinal stem cells initiate intestinal polyposis. Nat Genet. 2007;39:189–98.

    Article  CAS  Google Scholar 

  36. Singh A, Sharma A, Smith J, Krishnan M, Chen X, Eschrich S. et al. Claudin-1 up-regulates the repressor ZEB-1 to inhibit E-cadherin expression in colon cancer cells. Gastroenterology. 2011;141:2140–53.

    Article  CAS  Google Scholar 

  37. Balint K, Xiao M, Pinnix CC, Soma A, Veres I, Juhasz I. et al. Activation of Notch1 signaling is required for β-catenin–mediated human primary melanoma progression. J Clin Investig. 2005;115:3166–76.

    Article  CAS  Google Scholar 

  38. Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I. et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through Slug-induced repression of E-cadherin. J Exp Med. 2007;204:2935–48.

    Article  CAS  Google Scholar 

  39. Chassaing B, Aitken JD, Malleshappa M, Vijay-Kumar M. Dextran sulfate sodium (DSS)-induced colitis in mice. Curr Protoc Immunol. 2014;104:Unit 1525

    Google Scholar 

  40. Snider AJ, Bialkowska AB, Ghaleb AM, Yang VW, Obeid LM, Hannun YA. Murine model for colitis-associated cancer of the colon. Methods Mol Biol. 2016;1438:245–54.

    Article  CAS  Google Scholar 

  41. Erben U, Loddenkemper C, Doerfel K, Spieckermann S, Haller D, Heimesaat M. et al. A guide to histomorphological evaluation of intestinal inflammation in mouse models. Int J Clin Exp Pathol. 2014;7:4557–76.

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was supported by BX002086 (VA merit), CA216746 (NIH/NCI) and a pilot project award from Fred and Pamela Buffet Cancer Center, which is funded by a National Cancer Institute Cancer Center Support Grant under award number P30 CA036727 to P.D. and DK088902 (NIH/NIDDK) and BX002761 (VA merit) to A.B.S.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA

    Saiprasad Gowrikumar, Rizwan Ahmad, Srijayaprakash Babu Uppada, Amar B. Singh & Punita Dhawan

  2. Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA

    Mary K. Washington & Chanjuan Shi

  3. VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA

    Amar B. Singh & Punita Dhawan

  4. Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA

    Amar B. Singh & Punita Dhawan

Authors
  1. Saiprasad Gowrikumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rizwan Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Srijayaprakash Babu Uppada
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mary K. Washington
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chanjuan Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Amar B. Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Punita Dhawan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Punita Dhawan.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gowrikumar, S., Ahmad, R., Uppada, S.B. et al. Upregulated claudin-1 expression promotes colitis-associated cancer by promoting β-catenin phosphorylation and activation in Notch/p-AKT-dependent manner. Oncogene 38, 5321–5337 (2019). https://doi.org/10.1038/s41388-019-0795-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-019-0795-5

This article is cited by

Search

Advanced search

Quick links